Background
Definition of prognostic factors
Disease activity
Poor prognostic factor | Outcome | Study type | References |
---|---|---|---|
Increased DAS28 or single components | Radiographic progression Absence of remission | RCT, cohort Cohort | |
Increased MBDA | Radiographic progression | RCT, cohort | |
Presence or high titers of RF and/or ACPA | Radiographic progression Absence of remission | RCT, cohort Cohort | [42] |
Presence of erosions | Radiographic progression | RCT, cohort | |
Increased HAQ | Absence of remission Functional limitation | Cohort RCT | [13] |
Smoking | Radiographic progression | RCT | [15] |
Delayed diagnosis/treatment initiation | Absence of remission | Cohort | [16] |
Ultrasound Doppler activity | Radiographic progression Absence of remission | Cohort | |
MRI bone edema | Radiographic progression | RCT, cohort | |
Genetic predisposition (relatedness) | Radiographic damage | Cohort | [29] |
Trial | Inclusion criteria | Primary endpoint | Secondary endpoints |
---|---|---|---|
AGREE [45] | RA (1987) ≤2 years, MTX-naïve Poor prognosis: RF/ACPA-positive, SJC ≥10, TJC ≥12, CRP ≥4.5 mg/l, erosions | Remission (DAS28-CRP <2.6) Joint damage (TSS) at 1 year | ACR response DAS28-CRP HAQ-DI, HRQoL improvement Radiologic nonprogression |
TEAR [42] | RA (1987) <3 years, biologic DMARD-naïve Poor prognosis: RF/ACPA positive or radiologic erosions Active: SJC ≥4, TJC ≥4 (28 joints), DAS28-ESR >3.2 | DAS28-ESR at week 48 and 102 | ACR response Modified HAQ Joint damage |
C-EARLY [40] | RA (2010) ≤1 year, DMARD-naïve poor prognosis (RF/ACPA-positive) Active RA: SJC ≥4, TJC ≥4, DAS28-ESR >3.2, ESR ≥28 or CRP ≥10 mg/l | Sustained remission (DAS28-ESR <2.6) or low disease activity (<3.2) at week 40 and 52 | ACR response HAQ-DI TSS (change from baseline) At week 52 |
C-OPERA [6] | RA (2010) ≤1 year, MTX-naïve Poor prognosis (ACPA ≥3× upper limit of normal and RF-positive and/or erosions Active RA: DAS28-ESR ≥3.2 | Non-progression (defined: mTSS ≤0.5 change from baseline to 12 months) | SDAI, Boolean and DAS28-ESR HAQ-DI ACR response |
FUNCTION [41] | RA (1987) ≤2 years, MTX-naïve Poor prognosis: RF/ACPA-positive or radiologic erosions Active RA: DAS28-ESR >3.2, SJC ≥4 (66 joints), TJC ≥6 (68 joints), ESR ≥28 or CRP ≥10 mg/l | Remission (DAS28-ESR <2.6 at week 24 | ACR response Modified TSS SF-36 |
CareRA [46] | RA (1987) ≤1 year, DMARD-naïve Lack of poor prognosis: no erosions, DAS ≤3.2, seronegative | Remission (DAS28-CRP ≤3.2) at week 16 | EULAR response HAQ response Cumulative disease activity |
Serologic factors
Erosions
Functional limitation
Extraarticular disease
Smoking
Treatment response
Biomarkers
Protein biomarkers
Imaging biomarkers
Genetic biomarkers
Definition of outcomes
Validation of prognostic factors in RCT and cohort studies
Risk models
Validation studies
Current use of poor prognostic factors
Poor prognostic factors in treatment recommendations
RA state | Poor prognostic factors | Presence allows for | Treatment target | |
---|---|---|---|---|
EULAR [3] | RA, first DMARD failure | High disease activity, RF/ACPA positivity, early presence of joint damage | bDMARDs | Low disease activity or remission |
ACR [4] | Early RA <6 months | Moderate disease activity + ≥1 of functional limitation, extraarticular disease, RF/ACPA positivity, erosions | csDMARD combination | |
High disease activity + one or more of functional limitation, extra-articular disease, RF/ACPA positivity, erosions | bDMARD or csDMARD combination | |||
Established RA (≥6 months or 1987 ACR criteria) | LDA + one or more of functional limitation, extraarticular disease, RF/ACPA positivity, erosions or at least moderate disease activity | csDMARD combination, bDMARD at 3 months | ||
Italy [5] | RA, DMARD failure | 1. High disease activity (DAS28 > 5.1 for ≥1 months 2. Moderate disease activity (DAS >3.2) + ACPA/RF positive and elevated CRP or ESR, persistence of one or more swollen joint, bone erosions on X-rays, active synovitis with power Doppler signal 3. New erosions | bDMARD | |
France [35] | RA, DMARD failure | Existence or progression of structural damage, high clinical and/or laboratory activity, high RF/ACPA titers | bDMARD | |
Germany [34] | RA, 1st DMARD failure | High disease activity, RF/ACPA positivity, early presence of joint damage | bDMARD | |
Canada [36] | RA | Not further specified | Initial csDMARD combination |
Poor prognostic factors in randomized controlled trials
Stratification for prognosis
Value of prognostic factors and perspectives
-
The definition of poor prognostic markers depends on the targeted outcome, the methods of measurement, and the cut-off values. These heterogeneous data need to be harmonized when poor prognostic markers are incorporated in treatment recommendations.
-
What is the target of prognostic markers? Do we need to validate prognostic factors for remission or low disease activity rather than for structural damage? Or do we need a combined target that includes the absence of erosions, absence of disease activity, and the preservation of functional status?
-
Can high disease activity at baseline be regarded as a poor prognostic factor or is it rather active disease over time? Time-integrated DAS28-ESR values during the first year post baseline were assessed by Koga et al. [11]. Rapid progression was the outcome and for this target, time-integrated DAS28 was not predictive.
-
The incorporation of novel potential prognostic factors into risk models is requested by van der Helm-van Mil [1]. Multibiomarkers, imaging markers, and patient-reported outcomes are currently under investigation and it will be challenging to combine these factors into one predictive model.
-
The frequency of poor prognostic markers in representative RA cohorts has not been assessed in detail. There is a specific lack of information on the prevalence of single or combined prognostic markers and their relevance. It remains unclear whether patients with autoantibodies and erosions or only one of those markers have different outcomes regarding remission, function, or joint damage [2].
-
Should seronegative RA be treated differently? At the same level of inflammation, ACPA-negative patients have less joint damage and a lower probability of damage in newly affected joints than ACPA-positive patients. De Punder et al. [43] proposed that low disease activity might be a sufficiently strict treatment target for ACPA-negative patients to prevent progression of joint damage. But it is not evident whether this also applies for remission and functional preservation.